The central goal of this research project is to derive a series of new, genetically heterogeneous, specific-pathogen free (SPF) stocks of mice (Mus musculus doesticus) that differ in aging rate, age-adjusted disease incidence, and lifespan. The strategy is based upon theory and data suggesting that long-lived, slow-aging populations are likely to evolve in natural environments that are relatively free of hazards, such as dramatic climatic changes and predation. The main test populations will be developed from feral mice that have evolved on tropical islands relatively free of both natural predation and seasonal temperature shifts: Enewetak (En) and Pohnpei (Po). Control stocks will be prepared in parallel from a mainland population trapped in Idaho, from HET-C1 (a genetically heterogenous stock derived from a cross among inbred lines B6, D2, C3H, and BALB), and from an island population (Foula) in which selective pressures are likely to have mitigated against longevity-associated genotypes. Wild-caught mice will be brought to the university of Michigan and SPF stocks will be derived by embryo-transplant. The first generation progeny of the SPF stocks will be allowed to age until their natural death, to test the hypothesis than En and Po mice are long-lived relative to mainland, boreal, and laboratory-derived mice. Terminal necropsies will be performed on all mice, to test the hypothesis that the (expected) long lifespan of the En and Po stocks reflects retardation in the age-adjusted incidence rates of most or all forms of major late-life diseases. Two age-sensitive biomarkers (collagen breaktime and primary antibody response) will be measured in the aging mice to assess the hypothesis that the (expected) long lifespan of the En and Po mice is accompanied by a parallel delay in biochemical and physiological concomitants of aging. If successful, this project will accomplish two major objectives. First, it will provide a test of the hypothesis that there is detectable intraspecies variation at loci that influence aging rate in mammals. Secondly, it will provide extremely valuable new mouse strains for testing biochemical, physiological, and genetic hypotheses about the mechanisms of aging.